Bacillus anthracis, the causative agent of anthrax, produces two major virulence factors: the capsule and the anthrax toxin. Anthrax toxin is composed of three independent polypeptide moieties: the protective antigen (PA), the lethal factor (LF) and the edema factor (EF), which act in binary combinations. Anthrax toxin constitutes a typical A-B type toxin in the sense that LF and EF are endowed with enzymatic activities, the targets of which are cytoplasmic. Binding to the host cell and translocation of the enzymatic moieties into the cytoplasm are ensured by PA. Therefore, the role of PA is absolutely essential since neither LF nor EF exert any effect on mammalian cell in the absence of PA. Due to our long-standing interest and expertise in bacterial toxins and the recent bio-terrorist attack in the USA, we wish to contribute too a better understanding of the mode of action of the anthrax toxin. The aim of the present project is to study the interaction of PA with the target cell plasma membrane at the molecular level, to determine by what exact pathway the toxin is internalized by the cell and to identify the precise stage of the endocytic pathway where the enzymatic moieties must be translocated into the cytoplasm in order to reach their real target. To address these issue we will use morphological (microscopy), biochemical and cell biological approaches. Our combined expertise in cell biology, in bacterial toxins and in cellular microbiology will be a great asset in studying the anthrax-host cell interaction. These studies should not only increase our understanding of the mode of action of the anthrax toxin and thereby of anthrax pathogenesis but might also lead to the identification of potential therapeutical targets to treat the disease.